Nomogram for predicting severe abdominal pain after initial conventional transarterial chemoembolisation for hepatocellular carcinoma: a retrospective study

Transarterial chemoembolisation (TACE) is a standard therapy for hepatocellular carcinoma (HCC). However, adverse events, including abdominal pain, are common. This study aimed to investigate and verify the feasibility of a nomogram model to predict severe abdominal pain after first conventional TACE (cTACE) among patients with HCC. Patients with HCC treated with cTACE between October 28, 2019, and August 5, 2022, at a single centre were enrolled (n = 216). Patients were divided into training and validation cohorts (ratio, 7:3). A visual analogue scale score between 7 and 10 was considered severe abdominal pain. A total of 127 (58.8%) patients complained of severe abdominal pain after first cTACE treatment. The nomogram considered age and tumour number and size. The nomogram demonstrated good discrimination, with a C-index of 0.749 (95% confidence interval [CI], 0.617, 0.881). Further, the C-index in the validation cohort reached 0.728 (95% CI 0.592, 0.864). The calibration curves showed ideal agreement between the prediction and real observations, and the nomogram decision curve analysis performed well. The nomogram model can provide an accurate prediction of severe abdominal pain in patients with HCC after first cTACE, aiding in the personalization of pain management and providing novel insights into hospital nursing.


Pain assessment
Pain was assessed within 24 h after cTACE by using the visual analogue scale (VAS) score, which is a standard and checked ten-point scale for the self-reporting of pain 12 .Scores range from 0 to 10, with a score of 0 representing absence of pain and a score of 10 representing the highest pain level.Score between 1 and 3, 4 and 6, and 7 and 10 represented mild, moderate, and severe pain, respectively.When the pain level assessment is complete, we used acetaminophen, aminotriol ketorolate, and pethidine hydrochloride to relieve mild, moderate and severe pain respectively and immediately.

Clinical data collection
The following clinical characteristics were collected: sex, age, maximum tumour diameter or tumour size, portal vein thrombosis, duration of the procedure, white blood cell count, red blood cell count, haemoglobin, platelet count, α-fetoprotein, alanine transferase, and aspartate aminotransferase.Access to the hospital's medical record management system was used to obtain all data.Two investigators entered data simultaneously to ensure the accuracy of information.Two radiologists with a minimum of 5 years of experience independently reviewed all radiology images.If there were more than two tumours, patients were deemed to have multiple-lesion HCC, and the largest tumour, as indicated by diameter, was analysed.www.nature.com/scientificreports/A predictive nomogram was generated based on several independent factors evaluated by multivariate analysis using the R software version 3.2.0(The R Foundation for Statistical Computing, Vienna, Austria) and the 'rms' package.Moreover, the model was validated using 1000 bootstraps to quantify the overarching modelling strategy while assessing the model's prediction accuracy.Each statistical test in our study was two-sided, and P-values < 0.05 were used to indicate statistical significance.

Baseline characteristics
A total of 216 patients who underwent cTACE therapy were included in this analysis.Of these patients, 127 (58.8%) complained of severe abdominal pain after their initial cTACE.Of all patients who underwent cTACE therapy, 181 were men, and 35 were women.Most patients were younger than 65 years and had a tumour exceeding 5 cm in diameter.Portal vein tumour thrombi were present in 76 (35.1%) patients.The number of patients with α-fetoprotein levels above or below 400 ng/mL did not differ significantly between both groups.Additional details on patient characteristics are presented in Table 1.
Subsequently, we established a nomogram based on the significant risk factors identified by the univariate and multivariate analyses in the training set (Fig. 1).For each factor in the nomogram, a weighted number of points was calculated, and the sum of points for each patient was associated with a corresponding prediction of the presence of severe abdominal pain.A higher total score was associated with a higher rate of severe abdominal pain.For example, a 71-year-old man with a single 75-mm HCC nodule would have a total of 100 points (age, 0 points; tumour size, 100 points; and tumour number, 0 points).For this patient, the predicted incidence of severe abdominal pain was 38%.

Model performance and validation
The C-index of the nomogram within the training set was 0.749 (95% CI 0.617, 0.881).As seen in Fig. 2, the calibration curves in the training set demonstrated an optimal relationship.Furthermore, the calibration curves showed favourable calibration of the nomogram in the testing set (Fig. 3).The decision curve analysis (DCA) demonstrated that this nomogram had an added benefit in predicting severe abdominal pain as compared with treating all patients or treating no patient in the training and testing cohorts (Fig. 4).

Discussion
Although surgical resection and liver transplantation may cure HCC, but most of HCC patients are already in the middle and advanced stages at the time of diagnosis, and they are not suitable for radical resection.Systemic therapy, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), improved the prognosis for these patients in recent years.TACE is also an effective therapy and widely recommended as firstline therapy for intermediate and advanced HCC.However, the rate of adverse events after TACE is high.In our study, the probability of severe abdominal pain following the first cTACE procedure was as high as 58.8%, which is greater than the likelihood reported in other studies 13 .One possible reason for this is that our study included a relatively high number of younger patients than other studies.Bian et al. included other patients, including those undergoing their first TACE procedure, because a history of TACE procedure has been reported as a protective factor for post-embolisation abdominal pain 13 .The mechanisms underlying post-embolisation pain are still not completely understood.However, it is believed to be related to local tissue hypoxia, tumour necrosis, ectopic embolisation, and inflammatory response caused by cytokine release 14,15 .
Currently, few studies have explored the risk factors influencing the development of PES in patients with HCC after He et al. discovered that drug-loaded microsphere TACE and serum albumin could act as protective factors influencing PES, whereas drug loading was a risk factor for PES after the first TACE for patients with HCC 16 .Khalaf et al. illustrated the history of PES, tumour burden, and drug-eluting embolic TACE to be predictors affecting PES and, thus, constructed a predictive model for PES after TACE 17 .Moreover, Pachev et al. used VAS to identify factors predicting severe abdominal pain during and after TACE for HCC and found that age, liver cirrhosis, and alcoholic liver disease were negative predictive factors of severe abdominal pain 18 .However, to our knowledge, this study is the first to focus on the factors influencing severe post-embolisation abdominal pain after initial cTACE among patients with HCC and to establish a simple, easily applicable nomogram based on clinical characteristics.The nomogram displayed good discrimination power, with C-indices of 0.749 (95% CI 0.617, 0.881) in the training cohort and 0.728 (95% CI 0.592, 0.864) in the validation cohort.The calibration curves showed ideal agreement between the prediction and real observations.Finally, the DCA of nomograms performed well.
In our study, age, tumour number, and tumour size were independent predictors of severe abdominal pain, and thus construct the nomogram.These results provide clinically relevant information to help predict and proactively pain treatment, relieve patients' pain and therefore shorten their hospital stay.
According to the nomogram, the older the patient, the less severe the pain, which is consistent with the results of Pachev et al. 18 .The relationship between age and pain is complex and depends on the clinical situation.The most possible reason for this is that pressure nociception thresholds decrease with age 19 .Moreover, the tumour size and tumour number are referred to as tumour burden 20 .Our study found that higher tumour burden was indicative of more severe abdominal pain and was similar to that of Bian et al. in that patients with larger tumour sizes or multiple tumours required a longer procedure duration 13 .This is associated with drug dose and causes longer arterial spasms and more extended liver parenchymal necrosis, especially those of the bile ducts.Bile ducts are considered sensitive to oxygen deprivation 14,21 .cTACE treatment can cause various PES besides abdominal pain, including nausea, vomiting, chill, fever, liver infarction, liver abscess, heterotopic embolization, acute renal failure, acute hepatic failure, and so on.For the prevention of these complications, the dose of lipiodol should be well monitored and superselective chemoembolization is required 22,23 .Many previous studies have illustrated the risk factors of other TACE complications, such as acute hepatic failure or nausea and vomiting and have shown that liver enzymes is one of the main predictive risk factors 24,25 .But in our study, liver function (bilirubin, albumin, ALT, AST) levels were not associated with severe abdominal pain.
Our study has notable limitations.First, the sample size was relatively small, and the retrospective analysis has intrinsic limitations.Our nomogram model should, therefore, be verified by conducting a large prospective study and including other potential contributory factors.Moreover, most patients included in this study had an aetiology of hepatitis B virus infection.Thus, our nomogram model should be verified by including other HCC aetiologies.Furthermore, our model was not externally validated.Future studies with a larger sample size across multiple sites should be designed to confirm our findings.At last, our prediction model included only one complication, severe abdominal pain, and we will include others in future study.

Conclusions
In conclusion, we generated a nomogram to predict severe abdominal pain after cTACE in patients with HCC.A reliable and feasible non-invasive approach to predict severe post-embolisation abdominal pain in patients with HCC may improve treatment in clinical practice and provide personalized treatment.

6 ,
Xuhua Xiao 2,6 , Houxiang Ya 4,6 , Jinhai Li 3,6 , Fugang Liang 1 , Haiqing Jin 1 , Lianghuan Liao 1 , Yaohua Li 4 , Jiahui Qin 4 , Jue Yu 4 , Jing Gu 4 , Chunmei Zhou 4 , Ming Jin 5 , Ying Miao 5 & Shuqun Li 4* Transarterial chemoembolisation (TACE) is a standard therapy for hepatocellular carcinoma (HCC).However, adverse events, including abdominal pain, are common.This study aimed to investigate and verify the feasibility of a nomogram model to predict severe abdominal pain after first conventional TACE (cTACE) among patients with HCC.Patients with HCC treated with cTACE between October 28, 2019, and August 5, 2022, at a single centre were enrolled (n = 216).Patients were divided into training and validation cohorts (ratio, 7:3).A visual analogue scale score between 7 and 10 was considered severe abdominal pain.A total of 127 (58.8%) patients complained of severe abdominal pain after first cTACE treatment.The nomogram considered age and tumour number and size.The nomogram demonstrated good discrimination, with a C-index of 0.749 (95% confidence interval [CI], 0.617, 0.881).Further, the C-index in the validation cohort reached 0.728 (95% CI 0.592, 0.864).The calibration curves showed ideal agreement between the prediction and real observations, and the nomogram decision curve analysis performed well.The nomogram model can provide an accurate prediction of severe abdominal pain in patients with HCC after first cTACE, aiding in the personalization of pain management and providing novel insights into hospital nursing.

Figure 1 .Figure 2 .
Figure 1.Nomogram to predict severe abdominal pain after initial conventional transarterial chemoembolisation in the training set.

Figure 3 .
Figure 3. Receiver operating characteristic (A) and calibration curves (B) in the validation set.

Figure 4 .
Figure 4. Decision curve analysis for severe abdominal pain in the training set.
The statistical significance of the clinical factors was assessed by univariate analysis, and variables found to have statistical significance were included in the multivariate analysis using binary logistic regression to identify the risk factors associated with severe abdominal pain following cTACE.

Table 1 .
Baseline demographic and clinical characteristics of patients in the training and validation cohorts (n = 216).PVTT portal vein tumour thrombus, WBC white blood cell count, RBC red blood cell count, Hb haemoglobin, PLT platelet, AFP α-fetoprotein, ALT alanine transaminase, AST aspartate transaminase.

Table 2 .
Univariate and multivariate regression for severe abdominal pain after initial conventional transarterial chemoembolisation in the training cohort.Significant values are in bold.OR odds ratio, CI confidence interval, PVTT portal vein tumour thrombus, WBC white blood cell count, RBC red blood cell count, Hb haemoglobin, PLT platelet, AFP α-fetoprotein, ALT alanine transaminase, AST aspartate transaminase.